N-tritylimidazoles as antifungal agents

ABSTRACT

BIS-IMIDAZOLYL-BISPHENYLMETHANE AND PHARMACEUTICALLY ACCEPTABLE NON-TOXIC SALTS THEREOF ARE USEFUL AS ANTIMYCOTICS ESPECIALLY AGAINST DERMATOMYCOSIS CAUSED BY TRICHOPHYTON AND MICROSPORIUM SPECIES AND ALSO AGAINST YEAST INFECTIONS OF THE SKIN AND INTERNAL ORGANS

United States Patent 3,836,664 N -TRITYLIMIDAZOLES AS ANTIFUNGAL AGENTSErik K. Regel, Wuppertal-Kronenberg, Karl-Heinz Bucliel, Leverkusen, andManfred Plempel, Wuppertal-Elberfeld, Germany, assignors to BayerAktiengesellschaft, Leverkusen, Germany N0 Drawing. Application Oct. 8,1971, Ser. No. 187,814, which is a division of appplication Ser. No.873,098, Oct. 31, 1969. Divided and this application June 22, 1973, Ser.No. 372,807 Claims priority, application Germany, Nov. 5, 1963,

Int. Cl. A611; 27/00 US. Cl. 424-273 17 Claims ABSTRACT OF THEDISCLOSURE Bis-imidazolyl-bisphenylmethane and pharmaceuticallyacceptable non-toxic salts thereof are useful as antimycotics especiallyagainst dermatomycosis caused by T richophyton and Microsporium speciesand also against yeast infections of the skin and internal organs.

This application is a divisional of our copending application Ser. No.187,814 filed Oct. 8, 1971, which is a divisional of our prior-filedapplication Ser. No. 873,098 filed Oct. 31, 1969.

The present invention is concerned with bis-imidazolylbisphenylmethanes,salts thereof, processes for their production, pharmaceuticalcompositions containing such compounds and methods of treating fungalinfections pathogenic to humans and animals and methods of treatingyeast infections pathogenic to humans and animals. More particularly,the compounds of the present invention arebis-imidazolyl-bisphenylmethanes which may be substituted in one or bothof the imidazolyl moieties and one or both of the phenyl moieties.

The compounds of the present invention are particularly useful asantimycotics especially against dermatomycosis caused by Trichophytonand Microsporium species and also against yeast infections of the skinand internal organs.

The compounds of the present invention may be represented by theformula:

RJLL

wherein and includes salts of such compounds.

When R R or R is alkyl, it is preferred that the alkyl moiety containfrom 1 to 4 carbon atoms. When it is aryl, it is preferred that the arylmoiety contain up to carbon atoms in the ring system and the preferredaryl moiety is phenyl. The aryl may be substituted in which event thepreferred substituents are lower alkyl, S-alkyl or alkoxy, haloalkyl ofl to 4 carbon atoms in the alkyl portion and preferably 1 or 2 carbonatoms in the alkyl portion and wherein the halogen is preferablyfluorine, chlorine or bromine, or by an electronegative moiety,preferably a halogen.

When X or Y is alkyl, it is preferred that the alkyl moiety contain from1 to 12 carbon atoms and preferably 1 to 4 carbon atoms. When it isS-alkyl or alkoxy, it is preferred that the alkyl portions contain from1 to 4 carbon atoms. When it is an electronegative moiety, it ispreferred that the electronegative moiety be halogen, i.e. fluorine,chlorine, bromine or iodine, N0 CF or CN.

It is to be appreciated that when X or Y is more than one such moiety asabove defined, such as in the case where m or n is 2, that the moietiesmay be the same or different.

The term alkyl includes straight chain and branched chain alkyl moietiesas well as the saturated alkyl moieties and the partially unsaturatedmoieties, i.e. those containing a double bond.

The salts of the bis-imidazoly1bisphenylmethanes of the presentinvention are preferably pharmaceutically acceptable non-toxic salts andexamples of acids which give salts useful as hereinabove discussedinclude the halogen hydracids, phosphoric acids, monoand bifunctionalcarboxylic acids and hydroxycarboxylic acids, for example, acetic acid,propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid,citric acid, salicylic acid, sorbic acid and lactic acid and1,5-naphthalene-di-sulphonic acid. Of particular interest are thehydrohalides, particularly the chlorides, lactates and salicylates ofthe bis-imidazolyl-bisphenylmethanes.

According to a preferred embodiment of the present invention, R R and Rare hydrogen, X and Y are the same or different and are fluorine,chlorine, bromine, iodine, CN, N0 methoxy, thiomethyl or CE, and m and nare 1.

The bis-imidazolyl-bisphenylmethanes of the present invention may beproduced by reacting a diphenyl-dihalomethane of the formula:

Hal

X... Hal Y, (2)

wherein X, Y, m and n are as above defined and 'Wherein Hal is chlorine,bromine or iodine, with the stoichiometric amount of an imidazolederivative of the formula:

ll l wherein R R and R are as above defined, in the presence of an inertpolar solvent and of the stoichiometric amount of an acid acceptor, at atemperature range of from about 0 C. to about 100 C. It is preferredthat the reaction temperature be in the range of 50 C. to C.

Examples of suitable solvents are ketones, such as acetone, methyl ethylketone, diethyl ketone and as examples representing other types ofsolvents, dimethyl formamide, acetonitrile and nitromethane.

As acid acceptor two further equivalents of the imidazole derivative maybe used; however, the corresponding quantity of one of the conventionaltertiary amines is preferably used, such as triethylamine,dimethylanilin, N,N-dimethyl-benzylamine and the like.

The starting materials used for the process of the present invention,i.e. the diphenyl-dihalomethanes of the formula (2) and the imidazolederivatives of the formula (3) are known or can be obtained according tomethods and/or procedures per se known.

The following examples are representative of compounds of the formula(3') imidazole 2-methylimidazole 2-ethylimidazole Z-phenylimidazole 4,(5 -phenylimidazole 4,-5-diphenylimidazole benzimidazole Salts ofcompounds of the formula 1) may be converted into their correspondingsalts by techniques per se known. For example, 0.2 mol of abis-imidazolyl-bisphenylmethane may be dissolved with heating inacetonitrile, followed by the addition of 0.22 ml. D,L-lactic acid. Theresidue remaining after the solvent has been distilled off may be madeto crystallize by covering it, after filtration, with a layer of ether;the crystalline product may be washed with ether and dried.

The hydrochlorides are expediently obtained by introducing hydrogenchloride into the solution of the imidazole derivative, for example, incarbon tetrachloride.

The following table shows examples of the compounds of the invention:

Mp. C. (a) bis-imidazolyl-bis-phenylmethane 190 (b) bis-imidazolyl 4chlorophenyl-phenylmethane 140 (c)bis-imidazo1yl-4-fluorophenyl-phenylmethane 130 (d)bis-imidazolyl-2,4-difluoro-diphenylmethane 129 (e)bis-imidazolyl-2-chlorophenyl-phenylmethane 143 (f)bis-imidazolyl-3-chlorophenyl-phenylmethane 118 (g)bis-imidazolyl-4-cyanophenyl-phenylmethane 125 (h)bis-(2-methylimidazolyl)-4-chlorophenyl phenylmethane 215 The compoundsand salts of the formula (1) can be used, inter alia, in the form of anaqueous emulsion, sus- 5 pension or solution. It is also possible to usethe aqueous solutions of the salts of the above compounds.

The invention is illustrated by the following Examples.

EXAMPLE 1 Bis-imidazolyl-4-chlorophenyl-phenylmethane To a solution of27.2 g. (0.4 mol) imidazole and 40.4 g. (0.4 mol) triethylamine in 300ml. acetonitrile there are added dropwise 54 g. (0.2 mol)4-chlorophenyl-phenyl-dichloromethane. 'The triethylamine hydrochlorideformed starts to separate at room temperature. The mixture is heated at80 C. for 12 hours to complete the reaction. After cooling, the reactionmixture is stirred with 500 ml. benzene ari'd washed with water untilfree of salt. The benzene solution is dried over anhydrous sodiumsulphate, filtered and concentrated by evaporation; afterrecrystallisation of the crude product from acetontrile, there result 41g. of pure bis-imidazolyl-4-chlorophenylphenylmethane of m.p. 140 C.

6 C H ClN --mo1. weight 334.5. Calculated: C, 68.0%; -H, 4.5%; Cl,10.6%; N, 16.7%.

EXAMPLE 2 Bis-imidazolyl-4-fiuorophenyl-phenylmethane Into a solution of29.4 g. (0.43 mol) imidazole and 43.7 g. (0.43 mol) triethylamine in 300ml. acetonitrile there are added dropwise 55 g. (0.21 mol)4-fluorophenyl-phenyl-dichloromethane. Separation of thetriethylammonium chloride formed begins at room temperature. The mixtureis heated at C. for 132 hours to complete the reaction. After cooling,the reaction mixture is stirred with 500 ml. benzene and washed with.water until free of salt. The benzene solution is dried over anhydroussodium sulphate, filtered and evaporated; after recrystallisation of thecrude product from acetonitrile there result 42 g. pure bis-imidazolyl 4fluorophenyl-phenyl-methane of m.p. C.

C H FN mol. weight, 318. Calculated: C, 71.8%; H, 4.7%; F, 6.0%; N,17.6%. Found: C, 71.7%; H, 4.9%; F, 6.0%; N, 17.6%.

The following compounds of the formula (4) are prepared in a manneranalogous to that set forth in Example 2 by reacting the appropriatedilphenyl-dichloromethane from the list on pages 6 to 11 with theappropriate imidazole set forth on page 12.

EXAMPLES 3-9 The following compounds of the formula (5) are prepared ina manner analogous to that set forth in Example 2 by reacting theappropriate diphenyl-dichloromethane from the list in cols. 3, 4, and 5with the appropriate imidazole set forth in col. 5, Example 1.

EXAMPLES 1015 The following compounds of the formula*(6) are prepared ina manner analogous to that set forth in Examples 1 and 2 by reacting theappropriate diphenyl-dichloromethane from the list in cols. 3, 4, and 5with the appropriate imidazole set forth in col. 5, Example 1.

EXAMPLES 16-34 R1 ZN H CH 103 H CH 190 H C H 193 H CH3 215 H CH3 240 IIC H 148 II C 11 lZS 2-F 4-F C I'] a 250 4-F 4-F CH; 216 4-F 4-Cl CH 2214-F 4-N CH; 220 4-Cl 4-Cl CH3 220 Q-F 4-F C H5 20' 4-1" 4-Cl C 11 1T44-F 4-NO2 C111 197 4-C1 A-CI C -H; 200

THERAPEUTIC UTILITY (1) Effectiveness in vitro against human-pathogenicfungi 1. T richophyten mentagrophytes:

compound (a) 4 /ml. fungistatic. compound (b) 4 'y/ml. compound (c) 4/ml. compound ((1) 4 'y/ml. compound (e) 4 ml. compound (f) 4 'y/ml.compound (g) 40 1 ml.

2. Candida albicans: 100 'y/ ml.

3. Penicillium cm.: 20 'y/ml.

4. Aspergillus niger: 20 'y/ml.

5. Microsp. fel; 40 'y/ml.

The test medium was Milieu depreuve according to Sabouraud, incubationtemperature: 28 C.

Taking as example white mice infected i.v. with Candida albicans andAspergillus fumigatus, the new compounds [c.g. (a) to (h)], given orallyin doses of 50-100 mg./ kg. body weight once or twice daily over days,show good curative effects. Dependent upon the dosage, the rate ofsurvival of the animals thus treated amounted to 50 to 85%, of theuntreated control animals 0 to With the same dosage scheme and a therapyduration of 8 to 10 days, the development of dermatomycoses caused byTrichophyton and Microsporium species can be inhibited in mice andguinea pigs in an average of 70% of the infected animals; in comparisonwith the untreatedcontrol group, the infection proceeds in the remaining30% mildly and adheres for only a short period of time.

The topical-therapeutic application in the form of ointments andtinctures with a 1% content of active ingredient leads in guinea pigsinfected with dermatophytes to healing of the mycosis within 6 to 8 dayspost infection whereas in untreated control animals the dermatomycosishas an average duration of 28 to 31 days.

In vivo activity Similar results are obtained when, instead of thecompounds (a) to (h), the other new compounds or salts are used.

Of special interest for practical use are the compounds which areunsubstituted on the imidazole ring, but which may be substituted in onephenyl moiety by a halogen atom (preferably chlorine, fluorine, inthe0-, mor pposition, i.e. 2-, 3- or 4-position) as well as their saltswith hydrochloric acid, lactic acid or salicylic acid.

It is particularly envisaged that the compounds of the present inventionmay be used in the following manner:

(a) In human medicine:

1. Dermatomycoses caused by fungi of the species T richophytes,Microsporium, Epidermyphytes, Aspergillus, Candida albicans, and otheryeasts,

2. Organomycoses caused by yeasts, mould fungi and dermatophytes.

(b) In veterinary medicine:

Dermatomycoses and organomycoses caused by yeasts,

mould fungi and dermatophytes.

The therapeutical application can be effected orally or parenterally asWell as topically in the form of solutions (e.g. dimethyl.sulphoxide/glycerol/water 2:226), alcohol, preferably ethanol andisopropanol, bufier solutions, powders, creams, ointments and tablets.For topical application preferably a concentration of about from 0.5 to10% of effective ingredient is used.

For humans the dosage amounts on average to between about 50 and about100 mg./kg. body weight, preferably 50 to about mg./kg. body weight, atintervals of up to 12 hours for the duration of about 8 to about 10days.

However, it may of course be found desirable in some cases to deviatefrom the quantities indicated here, not only depending on the method ofapplication, but also on possible variations in individual reactions tothe compound or the kind of formulation and on the time or the intervalat which it is administered. It may thus be possible to manage with lessthan the abovementioned minimum amount in some cases, whereas in othercases the indicated upper limit may have to be exceeded. If largerquantities are administered, it may be advisable to dis tribute these inseveral individual doses over the day.

The compounds of the present invention may be used as such or incombination with pharmaceutically acceptable nontoxic inert diluents orcarriers. Suitable forms of application, in combination with variousinert carriers, are the followng: tablets, capsules, powders, sprays,aqueous suspensions, injectable solutions, elixirs, syrups and the like.Such carriers comprise solid diluents or fillers, a sterile aqueousmedium as well as non-toxic organic solvents and the like. Tabletsandthe like intended for oral use may, of course, be provided withsweetening additives and other conventional substances. Thetherapeutically active compound should generally be present at aconcentration of about 0.5 to percent by weight of the total mixture, inquantities which are sufficient to achieve the dosagerange mentionedabove.

For oral application, the tablets can obviously also contain additives,such as sodium citrate, calcium carbonate and dicalciumphosphatetogetherwith various other additives, such as starch, preferably potato starch,and the like, and binding agents, such as polyvinyl-pyrrolidine, gelatinand the like. Lubricants, such as magnesium stearate, sodium laurylsulphhate and talc may also be used concurrently for the production ofthe tablets. In the case of aqueous suspensions and/or elixirs which areintended for oral use, the active substance may be provided with variousagents to improve the flavour, colouring substances, emulsifiers and/orwith diluents, such as water, ethanol, propylene glycol, glycerol andsimilar compounds or combinations.

For parenteral application, solutions of the active substances in sesameor peanut oil, or in aqueous propylene glycol or N,N-dimethyl formamidecan be employed as well as sterile aqueous solutions in the case ofwatersoluble compounds. Aqueous solutions of this kind should bebuffered in the usual manner it necessary; furthermore, the liquiddiluent should be rendered isotonic from the start by the addition ofthe necessary amount of salt or glucose. Such aqueous solutions areparticularly suitable for intravenous, intramuscular and intraperitonealinjections.

Sterile aqueous media of this kind are prepared in known manner.

In mice, rats, rabbits, dogs and cats the LD of the compounds mentionedabove ranges from about 500 to 1000 mg./kg. body weight when orallyadministered.

The present invention also includes pharmaceutical compositionscomprising one or more compounds as hereinbefore described as the activeingredient in combination with a pharmaceutically acceptable non-toxicinert diluent or carrier.

The present invention further provides a medicament in unit dosage formwhich comprises at least one of the compounds hereinbefore describedeither alone or in combination with a pharmaceutically acceptable inertdiluent or carrier. The medicament may include a protective envelopecontaining the active compound and if used the diluent or carrier.

The term medicament in dosage unit form as used in the presentspecification means a medicament as defined above in the form ofdiscrete portions each containing a unit dose, or a multiple orsub-multiple of a unit dose of the active compound or compounds. Suchportions may, for example, be in monolithic coherent form, such astablets, suppositories, pills or dragees; in wrapped or concealed form,such as wrapped powders, cachets, sachets, or capsules; in ampoules,either free or as a sterile solution suitable for parenteral injection;or in any other form known to the art.

Besides the antimycotic activity the compounds show an activity againstpathogenic protozoa, e.g. Trypanosoma, Trichomonos, Entamoebahistolytica, malaria parasites, Toxoplasma and against bacteria, e.g.Staphylocci, Streptococci, Klebsiella, E. coli.

Further the compounds activate the granulation in wound healing and showa hypocholesterinaemic activity.

What is claimed:

1. A pharmaceutical composition useful for treating fungal infectionspathogenic to humans or animals which comprises an antifungal amount ofa compound of the formula 31 @-.Q X... N Y,,

-N wherein R is hydrogen or alkyl of 1 to 4 carbon atoms;

X and Y are alkoxy of 1 to 4 carbon atoms; and mis0,1or2andnislor2;ormislor2andnis0,1or2;

or a pharmaceutically acceptable non-toxic salt thereof, in combinationwith a pharmaceutically acceptable nontoxic inert diluent or carrier.

2. A pharmaceutical composition accordingto claim 1 wherein R ishydrogen.

3. A pharmaceutical composition according to claim 2 wherein m is 1 andn is 0.

4. A pharmaceutical composition according to claim 3 wherein X ismethoxy.

5. A pharmaceutical composition according to claim 4 wherein X is 4-OCH6. A pharmaceutical composition according to claim 1 in oraladministration form.

7. A pharmaceutical composition according to claim 1 in parenteraladministration form.

8. A pharmaceutical composition according to claim 1 in a form suitablefor topical application.

9. A method of treating fungal infections pathogenic to humans oranimals which comprises administering to a human or animal in need ofsaid treatment an antifungal amount of a compound of the formula LI/ 1aLIE wherein R is hydrogen or alkyl of 1 to 4 carbon atoms; X and Y arealkoxy of 1 to 4 carbon atoms; and mis0,1or2andnis1or2;ormislor2andnis0,1or2; or a pharmaceutically acceptable non-toxic saltthereof.

10. A method accordingto claim 9 wherein R is hydrogen.

11. A method according to claim 10 wherein m is 1 and n is 0.

12. A method according to claim 11 wherein X is methoXy.

13. A method according to claim 9 wherein said administration is indosage unit form.

14. A method according to claim 12 wherein X is 4-OOH 15. A methodaccording to claim 9 wherein said administration is oral.

16. A method according to claim 9 wherein said administration isparenteral.

17. A method according to claim 9 wherein Said administration is bytopical application.

References Cited UNITED STATES PATENTS 1/ 1963 Schindler 260309 5/ 1967Mussell et a1 260309 OTHER REFERENCES JEROME D. GOLDBERG, PrimaryExaminer UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENTNO. 3, 3 4 DATED September 17, 1974 *NVENTORB) 1 Erik Regel et al It iscertified that error appears in the above-identified patent and thatsaid LettersPatent are hereby corrected as shown below: 7

Change the title of the patent to read --BIS-IMIDAZOLYLBISPHENYLMETHANE, SALTS THEREOF AND PROCESSES FOR THEIR PRODUCTION--Signed and szalzd this Tenth Day of August 1976 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN A ff Commissioner oj'Parem: andTrademarks UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PatentNo. 3, 836, 664 Dated September 1-7, 1974 Inventor-(s) Erik K. Regal;Karl-Heinz Buchel; and Manfred Plempel It is certifiedthat error appearsin the above-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 1, lines 45 to 55, correct the structural formula to read:

1; 211 ZCQEEQY.

Signed and sealed this 22nd day of April 1975.

(FZAL ttest C. ZL 'IRSELALL DANE? RUTH C. Ill-l2 N Commissioner ofPatents attesting Officer and Trademarks FDRM PC4050 (10-69) USCOMM-Dc60376-969 Q no. muslin? PIIIITIIIG omcl nu o-au-su.

